Vorapaxar in the secondary prevention of atherothrombotic events

TRA 2P–TIMI 50 Steering Committee and Investigators

Research output: Contribution to journalArticle

573 Citations (Scopus)

Abstract

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)

Original languageEnglish (US)
Pages (from-to)1404-1413
Number of pages10
JournalNew England Journal of Medicine
Volume366
Issue number15
DOIs
StatePublished - Apr 12 2012

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Secondary Prevention
Placebos
Intracranial Hemorrhages
Stroke
Myocardial Infarction
Confidence Intervals
Thrombin
Clinical Trials Data Monitoring Committees
PAR-1 Receptor
Hemorrhage
vorapaxar
Peripheral Arterial Disease
Platelet Aggregation Inhibitors
Cause of Death
Atherosclerosis
Blood Platelets
Ischemia
Therapeutics

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Vorapaxar in the secondary prevention of atherothrombotic events. / TRA 2P–TIMI 50 Steering Committee and Investigators.

In: New England Journal of Medicine, Vol. 366, No. 15, 12.04.2012, p. 1404-1413.

Research output: Contribution to journalArticle

TRA 2P–TIMI 50 Steering Committee and Investigators 2012, 'Vorapaxar in the secondary prevention of atherothrombotic events', New England Journal of Medicine, vol. 366, no. 15, pp. 1404-1413. https://doi.org/10.1056/NEJMoa1200933
TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. New England Journal of Medicine. 2012 Apr 12;366(15):1404-1413. https://doi.org/10.1056/NEJMoa1200933
TRA 2P–TIMI 50 Steering Committee and Investigators. / Vorapaxar in the secondary prevention of atherothrombotic events. In: New England Journal of Medicine. 2012 ; Vol. 366, No. 15. pp. 1404-1413.
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abstract = "BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3{\%}) in the vorapaxar group and in 1176 patients (10.5{\%}) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95{\%} confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2{\%}) in the vorapaxar group and 1417 patients (12.4{\%}) in the placebo group (hazard ratio, 0.88; 95{\%} CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2{\%} of patients who received vorapaxar and 2.5{\%} of those who received placebo (hazard ratio, 1.66; 95{\%} CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0{\%}, vs. 0.5{\%} in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)",
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TY - JOUR

T1 - Vorapaxar in the secondary prevention of atherothrombotic events

AU - TRA 2P–TIMI 50 Steering Committee and Investigators

AU - Morrow, David A.

AU - Braunwald, Eugene

AU - Bonaca, Marc P.

AU - Ameriso, Sebastian F.

AU - Dalby, Anthony J.

AU - Fish, Mary Polly

AU - Fox, Keith A.A.

AU - Lipka, Leslie J.

AU - Liu, Xuan

AU - Nicolau, José Carlos

AU - Ophuis, A. J.Oude

AU - Paolasso, Ernesto

AU - Scirica, Benjamin M.

AU - Spinar, Jindrich

AU - Theroux, Pierre

AU - Wiviott, Stephen D.

AU - Strony, John

AU - Murphy, Sabina A.

AU - McCabe, C. H.

AU - Morin, S.

AU - Lamp, J.

AU - Gershman, E.

AU - Deenadayalu, N.

AU - Skene, A.

AU - Hill, K.

AU - Bennett, L.

AU - Plat, F.

AU - Berman, G.

AU - Kilian, A.

AU - He, W.

AU - Aylward, P.

AU - Bassand, J. P.

AU - Betriu, A.

AU - Bounameaux, H.

AU - Corbalan, R.

AU - Creager, M.

AU - De Ferrari, G.

AU - Dellborg, M.

AU - Diehm, C. H.

AU - Dietz, R.

AU - Goto, S.

AU - Grande, P.

AU - Hankey, G.

AU - Isaza, D.

AU - Jensen, P.

AU - Kiss, R.

AU - Lewis, B.

AU - Merlini, P.

AU - Moliterno, D.

AU - DelCore, M.

PY - 2012/4/12

Y1 - 2012/4/12

N2 - BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)

AB - BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS:Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)

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DO - 10.1056/NEJMoa1200933

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